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TARGETING HUMAN BASE EXCISION REPAIR AS A NOVEL STRATEGY IN
CANCER THERAPEUTICS
by
Zahrah Zawahir
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2009
Copyright 2009 Zahrah Zawahir

APE1 is an attractive target for the rational design of small-molecule inhibitors in the field of oncological therapeutic research. It is an essential enzyme in the mammalian base excision repair pathway, and works in conjunction with other cellular proteins in the repair of abasic sites within the genome. This enzyme has been implicated in the resistance of tumors to current chemotherapeutic agents. Extensive effort is underway in the identification and development of clinically suitable inhibitors to this essential enzyme. Herein, we present the discovery of a series of inhibitors to APE1, as well as the identification of a novel class of bioisosteric compounds that inhibit the catalytic activity of the enzyme. We have also performed preliminary work in the development and optimization of biochemical models of APE1 expression regulation. This is an ongoing effort to characterize appropriate cellular systems in colon cancer for the development of cellular APE1 inhibitors that can be measured using valid biochemical endpoints. Interesting observations have been made in this regard, for the first time, also implicating the base excision repair pathway in the repair of platinum-agent induced DNA damage. Finally, as validation for APE1 as a therapeutic target, we studied the impact of single nucleotide polymorphisms in two populations of colorectal cancer patients, and found that the D148E polymorphism confers a measure of survival to males possessing it.

TARGETING HUMAN BASE EXCISION REPAIR AS A NOVEL STRATEGY IN
CANCER THERAPEUTICS
by
Zahrah Zawahir
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2009
Copyright 2009 Zahrah Zawahir